CN101883570A - Novel synthesis of beta-nucleosides - Google Patents

Novel synthesis of beta-nucleosides Download PDF

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CN101883570A
CN101883570A CN2008801189598A CN200880118959A CN101883570A CN 101883570 A CN101883570 A CN 101883570A CN 2008801189598 A CN2008801189598 A CN 2008801189598A CN 200880118959 A CN200880118959 A CN 200880118959A CN 101883570 A CN101883570 A CN 101883570A
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C-Y·朱
W-D·李
W·李
C·K·黄
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Abstract

This invention relates to a process of stereoselectively synthesizing -nucleoside, e.g., 2'-deoxy-2,2'-difluorocytidine.

Description

The novelty of beta-nucleosides is synthetic
The cross reference of related application
The application requires the U.S. Provisional Application 60/985,754 that proposes on November 6th, 2007 and the priority of the U.S. Provisional Application 61/023,566 that proposes on January 25th, 2008.The content of two provisional application of the complete introducing of this paper as a reference.
Background technology
2 '-deoxynucleoside and analog thereof are that important medicament is gone up in treatment.For example, gemcitabine (gemcitabine), that is, 2 '-deoxidation-2,2 '-difluoro cytidine can be used for treating viral infection and cancer.Referring to, for example, United States Patent (USP) 4,526,988 and 4,808,614.
Generally speaking, each 2 '-deoxynucleoside has more than one chiral centre and can occur with multiple stereoisomer.Not that whole stereoisomers all have therapeutic activity.Some stereo selectivity synthetic routes have been developed for 2-deoxidation-beta-nucleosides.Wherein not gratifying.
Need exploitation at the Stereoselective Synthetic 2 '-the more effective route of deoxynucleoside.
Summary of the invention
An aspect of of the present present invention relates to a kind of method of beta-nucleosides chemical compound of synthetic formula I:
Figure GPA00001146396200011
Wherein, R 1Be H, alkyl, aryl alkyl, alkyl diaryl silicyl, trialkylsilkl, diarye silyl, alkyl-carbonyl or aryl carbonyl; R 2For RC (O)-, RR ' NC (O)-, ROC (O)-, RC (S)-, RR ' NC (S)-or ROC (S)-; R and R ' are H, alkyl, aryl, cycloalkyl, Heterocyclylalkyl or heteroaryl independently of one another; R 3And R 4Be H or fluorine independently of one another; And B is
Figure GPA00001146396200021
Wherein, R 5Be H, alkyl or aryl; R 6Be H, alkyl, thiazolinyl, halogen or aryl; X is N or C-R ", R " be H, alkyl, thiazolinyl, halogen or aryl; And Y is an amino protecting group.This method is included in transition metal salt and exists down, makes the tetrahydrofuran-compound of formula II:
Figure GPA00001146396200022
Wherein, R 1, R 2, R 3And R 4As above-mentioned definition; L is fluorine, chlorine, bromine or iodine, and the nucleobase derivatives of following formula reaction:
Figure GPA00001146396200023
Wherein, R 5, R 6With Y such as above-mentioned definition, and Z is a hydroxyl protecting group.Above-mentioned reaction can be carried out under 25-100 ℃.
About formula I, the subclass (subset) of the beta-nucleosides chemical compound of this formula has one or more following features: R 1Be trityl, (CH 3) 3C, alkyl diaryl silicyl, trialkylsilkl or diarye silyl, R 2Be alkyl-C (O)-or aryl-C (O) (for example, PhC (O)-), and R 3And R 4The fluorine of respectively doing for oneself.About formula II, it is I that the subclass of the tetrahydrofuran-compound of this formula has one or more following features: L, and R 1Be trityl, (CH 3) 3C, alkyl diaryl silicyl, trialkylsilkl or diarye silyl, R 2Be alkyl-C (O)-or aryl-C (O) (for example, benzoyl), and R 3And R 4The fluorine of respectively doing for oneself.The feature of above-mentioned nucleobase derivatives can be R 5And R 6The trimethyl silyl (TMS) of respectively doing for oneself.
An example of said method is for making At AgClO 4, AgNO 3Or Ag 2CO 3There is reaction down, to form
Figure GPA00001146396200032
Method of the present invention can further comprise the chemical compound that the beta-nucleosides chemical compound is changed into formula III:
Figure GPA00001146396200033
Wherein, R 3, R 4With B such as above-mentioned definition.
In said method, the preparation of the chemical compound tetrahydrofuran derivatives of formula II can be by making down the lactone compound of formula IV:
Figure GPA00001146396200034
Wherein, R 3, R 4With B such as above-mentioned definition, be reduced into the furanose chemical compound of following formula:
Figure GPA00001146396200035
Wherein, R 3, R 4With B such as above-mentioned definition, again this furanose chemical compound is changed into the tetrahydrofuran-compound of formula II.The preparation of the chemical compound of formula IV, can pass through the chemical compound of elder generation with the acid treatment following formula:
Figure GPA00001146396200036
Wherein, R 3And R 4Be H or halogen independently of one another; R 7Be H, alkyl, aryl, cycloalkyl, assorted alkyl or heteroaryl; And R 8And R 9Be H or hydroxyl protecting group independently of one another, or R 8And R 9Be C together 1-3Alkylidene makes then from the chemical compound reaction of the product and the following formula of above-mentioned processing generation:
R 1-L’，
Wherein, R 1Be alkyl, aryl alkyl, alkyl diaryl silicyl, trialkylsilkl, diarye silyl, alkyl-carbonyl or aryl carbonyl; And L ' is leaving group, with the chemical compound of production (V):
Figure GPA00001146396200041
Wherein, R 1, R 3And R 4As above-mentioned definition, use R at last 2Come the free OH in protection (V) chemical compound.When direct substitution or ionizing, leaving group can be in its a plurality of covalent bonds one be with electron pair break away from (referring to, for example, F.A.Carey and R.J.Sundberg, Advanced Organic Chemistry, the 3rd edition, Plenum publishing house, 1990).The example of leaving group includes but not limited to, methanesulfonate, trifluoromethanesulfonic acid root, p-methyl benzenesulfonic acid root, iodine root, bromine root, chlorine root and trifluoroacetic acid root.
Another aspect of the present invention relates to the intermediate product that is used for said method.A kind of in this intermediate product has formula VI as follows:
Figure GPA00001146396200042
In this formula, R 1Be the hydroxyl protecting group of large volume, for example trityl (that is trityl group), (CH 3) 3C, alkyl diaryl silicyl, trialkylsilkl or diarye silyl; R 2Be H, alkyl-carbonyl or aryl carbonyl; And R 3And R 4Be H or halogen independently of one another.
About above-mentioned formula VI, a subclass of the chemical compound that this formula contained is characterised in that R 1Be trityl, R 2Be H or benzoyl, or R 3And R 4The fluorine of respectively doing for oneself.An example is shown in chemical compound 1:
Figure GPA00001146396200051
Other intermediate product has formula as follows (VII):
In this formula, R 2' be alkyl-carbonyl or aryl carbonyl, R 3And R 4Be H or halogen independently of one another, and B is
Figure GPA00001146396200053
Wherein, R 5Be H, alkyl or aryl; R 6Be H, alkyl, thiazolinyl, halogen or aryl; X is N or C-R ', and R ' is H, alkyl, thiazolinyl, halogen or aryl; And Y is an amino protecting group.
About above-mentioned formula II, a subclass of the chemical compound that this formula contained is characterised in that R 2' be benzoyl or acetyl group, R 3And R 4The fluorine of respectively doing for oneself, or B is
Figure GPA00001146396200054
An example is shown in following chemical compound 2:
Figure GPA00001146396200055
Term " alkyl " refers to comprise the straight or branched hydrocarbon of 1-6 carbon atom.The example of alkyl includes but not limited to, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group and the tert-butyl group.Term " alkoxyl " refers to the O-alkyl group.The example of alkoxyl includes but not limited to, methoxyl group, ethyoxyl and butoxy.Term " alkylidene " refers to alkyl two groups.The example of " alkylidene " includes but not limited to, methylene and ethylidene.
Term " thiazolinyl " refers to have the straight or branched hydrocarbon of one or more carbon-to-carbon double bonds.The example of thiazolinyl includes but not limited to, vinyl, 1-butylene base and crotyl.
Term " aryl alkyl " refers to have the moieties of one or more aryl substituents.The example of aryl alkyl includes but not limited to, benzyl and trityl (that is Ph, 3C).
Term " aryl " refers to 6-carbon monocycle, 10-carbon dicyclo, 14-carbon three cyclophane loop systems.The example of aryl includes but not limited to, phenyl, naphthyl and anthryl.
Term " alkoxy carbonyl " refers to alkyl-O-carbonyl group.The example of alkoxy carbonyl includes but not limited to, methoxycarbonyl, ethoxy carbonyl and tert-butoxycarbonyl.Term " aryloxycarbonyl " refers to aryl-O-carbonyl group.The example of aryloxycarbonyl includes but not limited to, phenyloxycarbonyl and 1-naphthoxy carbonyl.Term " amino carbonyl " refers to (R) (R ') N-carbonyl group, and wherein, R and R ' are H, alkyl or aryl independently of one another.Aminocarboxy example includes but not limited to, dimethylamino carbonyl, Methylethyl amino carbonyl and phenyl amino carbonyl.
The alkyl of mentioning herein, aryl, thiazolinyl and alkoxyl comprise the part that is substituted and is unsubstituted.Substituent example includes but not limited to; halogen, hydroxyl, amino, cyano group, nitro, sulfydryl, alkoxy carbonyl, acylamino-, carboxyl, alkyl sulphonyl, alkyl-carbonyl, urea groups, carbamoyl, carboxyl, ghiourea group, thiocyano, sulfonamido, alkyl, thiazolinyl, alkynyl, alkoxyl, aryl, heteroaryl, cyclic group and heterocyclic radical; wherein, alkyl, thiazolinyl, alkynyl, alkoxyl, aryl, heteroaryl, cyclic group and heterocyclic radical can be through further replacements.
Term " furanose " refers to the five-membered ring acetal form of sugar.
Other feature, target and advantage of the present invention is from following detailed description and what is claimed is significantly.
The specific embodiment
The present invention relates to a kind of Stereoselective Synthetic 2 '-effective ways of deoxynucleoside, more particularly, gemcitabine, and the novel intermediate product that produces in the method.
Conventional chemical conversion can be used for implementing the present invention.Those skilled in the art can determine to be used for suitable chemical agent, solvent, protecting group and the reaction condition of these chemical conversion.Relevant information is described in, for example, and R.Larock, Comprehensive OrganicTransformations, VCH publisher (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, the 3rd edition, John Wiley andSons (1999); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents forOrganic Synthesis, John Wiley and Sons (1994); Reach the Encyclopedia of Reagents for Organic Synthesis that L.Paquette edits, John Wiley andSons (1995) and subsequent editions thereof.For the example illustrative purposes, this paper has described the specific embodiment of the inventive method.
As institute's diagrammatic illustration in the following route map 1, chemical compound 1 of the present invention can be synthetic from chemical compound 3 (it can prepare by known method).Referring to, for example, L.W.Hertel US 4,526,988 or T.S.Chou wait the people, Synthesis, 1992,565-570.The removal of the acetonide in the chemical compound 3 (acetonide) can at high temperature be carried out with trifluoroacetic acid in the mixture of suitable organic solvent and water, to produce trihydroxy-valerate 4,3, the mixture of 5-dihydroxy lactone 5 and trihydroxy-valeric acid 6.This mixture is then handled with trityl chloride under 100 ℃ the temperature and is provided 5-lactone 1 through protection with high yield being lower than.This lactone 1 can not purifiedly be used for ensuing reactions steps.
Route map 1
Figure GPA00001146396200071
Following route map 2 shows a kind of route by chemical compound 1 synthetic beta-nucleosides chemical compound.
Route map 2
Figure GPA00001146396200081
X '=OH, Cl, Br, O-alkyl sulphonyl or O-aryl sulfonyl
Figure GPA00001146396200082
The hydroxyl of chemical compound 1 is at first protected and form corresponding benzoate 7, and it is reduced agent and changes into furanose 8.Chemical compound 8 to the conversion of iodide 10 can be carried out in two ways.A kind of for making furanose 8 and I 2In the presence of trialkyl phosphine or trialkyl phosphite and alkali, react.Another kind of for furanose 8 being changed into corresponding chloride, bromide, alkyl sulfonic ester and aromatic yl sulphonate 9, between methane sulfonate that is producing under the high temperature and iodide (for example sodium iodide, lithium iodide, potassium iodide or iodate tetra-allkylammonium), react subsequently.Then, iodide 10 can be used for by with nuclear base prepared in reaction nucleoside.For example, as implied above, iodide 10 produce beta-nucleosides 11 with the nuclear base reaction of TMS-protection, and this beta-nucleosides 11 is optionally gone protection and produces 3-benzoyl-gemcitabine 2.The selectivity of chemical compound 11 removes further enrichment beta-anomer-(that is, chemical compound 2) of protection.Can produce gemcitabine with alkali to the saponification of chemical compound 2.
The invention is characterized in that the end group heterogeneous mixture (that is alpha-anomer: the ratio of beta-anomer-is about 1: 1) by iodide 10 prepares beta-nucleosides 11 as primary product.Be not limited by theory, this reaction can be carried out the S shown in the route map 3 N1 mechanism and obtain the spatial chemistry of beta-nucleosides 11.As follows, the iodine atom, a kind of good leaving group breaks away from from chemical compound 10, the result, chemical compound becomes the cation intermediate product.This breaks away from by transition metal ions (Ag for example +) promote.This cation intermediate product is stable by the ester group of the C-3 position of oxolane ring by forming six-membered cyclic oxygen.Because this ester group is positioned at the bottom of oxolane ring, so six-membered cyclic oxygen also is to be positioned at the bottom.As a result, the nuclear base portion is attacked oxygen from the top of oxolane ring, so that steric hindrance minimizes, provides beta-nucleosides 11 thus.
Route map 3
Figure GPA00001146396200091
In order to implement the present invention, need protection and remove resist technology.For example, route map is presented at and uses hydroxyl and amino protecting group in the synthesizing gemcitabine.That is, above the furanose shown in comprises two hydroxyl protecting groups, and above the nuclear base shown in then comprises amino protecting group.Protecting group refers to that in a single day those connect active part (for example, hydroxyl or amino), prevents the group that these parts are disturbed and can be removed by conventional method after reaction by reaction afterwards.The example of hydroxyl protecting group includes but not limited to; alkyl, benzyl, pi-allyl, trityl are (promptly; trityl group), acyl group (for example; benzoyl, acetyl group or HOOC-X "-CO-; X " be alkylidene, alkylene group, cycloalkylidene or arlydene), silicyl (for example; trimethyl silyl, triethylsilyl and t-butyldimethylsilyl), alkoxy carbonyl, amino carbonyl (for example, dimethylamino carbonyl, methyl B aminocarbonyl and phenyl amino carbonyl), alkoxyl-methyl, benzene methoxyl methyl and alkyl mercapto methyl.The example of amino protecting group includes but not limited to, alkyl, acyl group and silicyl.Hydroxyl and amino protecting group are at T.W.Greene and P.G..M.Wuts, and Protective Groups in Organic Synthesis, discusses among the JohnWiley and Sons (1991) by the 2nd edition.Hydroxyl and amino protecting group all can be removed by conventional method after reaction.
For above-mentioned synthetic method, finishing of reaction can be monitored by the method for any routine, for example, and ultraviolet spectrogram, infrared spectrum, nuclear magnetic resonance, NMR, thin layer chromatography, gas chromatography and high performance liquid chromatography.After reaction was finished, product can not purifiedly easily use because its productive rate is high, or product can pass through one or more conventional separation methods (for example chromatograph, recrystallization, extraction or distillation) and separates from reactant mixture.This product can be further purified to produce higher enantiomeric purity by known method in the document.Referring to, for example, United States Patent (USP) 5,223,608.Chemical compound of the present invention can maybe can be purified not having under the purification to use, for example recrystallize or the chromatograph by with an organic solvent.
Below specific example be interpreted as only being used as example explanation, and limit the remainder of present disclosure never in any form.Under the situation that does not have further elaboration, can think: those skilled in the art can utilize the present invention's degree extremely the most completely according to the description of this paper.All publications of enumerating herein of the complete introducing of this paper, as a reference.
Synthesizing of gemcitabine
(1) 3-(2,2-dimethyl-1,3-dioxolanes-4-yl)-2, the purification of 2-two fluoro-3-hydroxypentanoic acid ethyl esters.
Figure GPA00001146396200101
R=methyl or ethyl
According to method described in the U.S. Patent application 11/416,380, prepare rough 3-(2,2-dimethyl-1,3-dioxolanes-4-yl)-2,2-two fluoro-3-hydroxypentanoic acid ethyl esters 12 (8 gram).Before use, it is by using hexane/CH 2Cl 2The silica gel chromatography purification of/EtOAc eluting, the mixture of the two that (the 3S)-alcohol 14 and 0.5 that restrains with (the 3R)-alcohol 13,0.9 that produces 4.6 grams restrains.
(2) preparation of 5-trityl-(3R)-hydroxyl-delta-lactone (chemical compound 1)
Figure GPA00001146396200111
Pure (3R)-hydroxyl valerate 3 (216 gram, 850 mMs), acetonitrile (1200 milliliters), water (60 milliliters) and trifluoroacetic acid (16 milliliters) are packed in 2 liter of two neck round-bottomed flask, be heated to 70～75 ℃ through 3-4 hour under the stirring then.This solution is cooled to ambient temperature.Except that after desolvating, residue and toluene (2x100 milliliter) azeotropic.
The residue that produces is placed under the vacuum.Add trityl group chlorine (trityl chloride at ambient temperature in proper order to its (comprising 4,5 and 6), 250.5 gram, 1.06 equivalent, 901 mMs), anhydrous EtOAc (600 milliliters), DMAP (1.0 grams, 0.01 equivalent, 8.5 mM) and pyridine (72.9 milliliters, 1.06 equivalents, 901 mMs).Suspension was heated to 55 ℃ (interior temperature) about 6 to 16 hours, be cooled to then 0 ℃ 1 hour.Mixture then filters through Celite pad, and washes this pad with cold EtOAc.Filtrate with merging of chemical compound 1 is used for following step.
The 5-trityl-(3R)-hydroxyl-2,2-difluoro delta-lactone: H 1NMR (CDCl 3): δ 3.41-3.45 (dd, 1H), 3.63-3.3.66 (dd, 1H), 4.45 (m, 1H), 4.53 (m, 1H), 7.25-7.55 (m, 15H).
(3) preparation of 5-trityl-3-benzoyl-delta-lactone.
Figure GPA00001146396200112
5-trityl-delta-lactone 1 is cooled to 5-10 ℃ in the solution of EtOAc.DMAP (1.0 grams, 0.01 equivalent, 8.5 mMs) and pyridine (78.6 milliliters, 1.1 equivalents, 935 mMs) order are added this solution, then dropwise add benzoyl chlorine.In adition process, interior temperature keeps below 8 ℃.Remove cooling bath, and stirred the mixture at ambient temperature 16 hours, mixture is cooled to 0 ℃ then.The mixture that produces filters through Celite pad, and washes this pad with cold EtOAc.The filtrate that concentrates merging is to produce the 5-trityl-3-benzoyl-delta-lactones 7 of 405.35 grams.H 1NMR(CDCl 3)：δ3.49-3.53(dd，1H)，3.67-3.3.71(dd，1H)，4.74(m，1H)，5.81(m，1H)，7.25-7.55(m，20H)。
H 1?NMR(CDCl 3)：δ3.27(d，1H，OH)，3.44(m，2H)，4.58(m，1H)，5.50(m，1H)，5.89(m，1H)，7.2-8.1(m，20H)。
(4) benzoic acid (2R, 3R)-4, the preparation of 4-two fluoro-5-hydroxyl-2-(triphen methoxy) oxolanes-3-base ester
Figure GPA00001146396200121
Under blanket of nitrogen, by t-butyl methyl ether (1970 milliliters) 5-trityl-3-benzoyl-delta-lactone 7 (405.35 gram, 788.6 mMs) is transferred to 5 liters two neck round-bottomed flasks or three neck round-bottomed flasks.The interpolation funnel that is connected to 5 liters of flasks has been loaded red aluminum (Red-Al) (238.83 milliliters, 1.06 equivalents, 836 mMs).Under 0 ℃, in 80 minutes, solution is dropwise added the solution of above-mentioned lactone 7, simultaneously interior temperature is remained in 3-8 ℃.
Add finish after, with the solution restir that produces 20 minutes.Under this temperature, 2-aminopropane. (75.5 milliliters, 982.5 mMs) is added solution so far, then dropwise add the aqueous solution (1360 milliliters) of 20% disodium tartrate dihydrate, simultaneously interior temperature is remained below 8 ℃.After adding is finished, stir the mixture up to observing two isolating layers.With EtOAc (2x500 milliliter) aqueous layer extracted.With the organic layer that saline (2x100 milliliter) washing merges, process MgSO 4Drying, filter and concentrate with the benzoic acid that produces 395 grams (765.5 mM) (2R, 3R)-4,4-two fluoro-5-hydroxyl-2-(triphen methoxy) oxolanes-3-base ester 8.H 1NMR(CDCl 3)：δ3.27(d，1H，OH)，3.44(m，2H)，4.58(m，1H)，5.50(m，1H)，5.89(m，1H)，7.2-8.1(m，20H)。
(5) benzoic acid (2R, 3R)-4, the preparation of 4-two fluoro-5-(mesyloxy)-2-(triphen methoxy) oxolanes-3-base ester
Under～0 ℃, with 5-trityl-3-benzoyl lactonaphthol 8 (220 gram, 426.4 mMs) and dichloromethane (880 milliliters) the two neck round-bottomed flasks of packing into.With Et 3N (64.7 grams, 639.6 mMs) adds to the solution of generation, then dropwise adds mesyl chloride (73.2 grams, 639.6 mMs) and is lower than 10 ℃ in the solution of dichloromethane (88 milliliters) with temperature in keeping.The solution restir that produces after 1 hour, is added saline (200 milliliters).Layer is separated.With organic layer process MgSO 4Drying is filtered, and concentrates to produce the rough methane sulfonate 9 of 334.4 grams.H 1NMR(CDCl 3)：δ3.02(s，3H)，3.56(m，2H)，4.50(m，1H)，5.60(dd，1H)，6.03(d，1H)，7.21-8.15(m，20H)。
(6) benzoic acid (2R, 3R)-4, the preparation of 4-two fluoro-5-iodo-2-(triphen methoxy) oxolanes-3-base ester
Take two kinds of methods from chemical compound 8 preparation benzoic acid (2R, 3R)-4,4-two fluoro-5-iodo-2-(triphen methoxy) oxolanes-3-base ester 10.
Method 1:
With benzoic acid (2R, 3R)-4,4-two fluoro-5-(mesyloxy)-2-(triphen methoxy) oxolanes-3-base ester 9 (2 grams, 3.37 mMs), acetone (20 milliliters) and NaI (5 the restrain 33.56 mMs) round-bottomed flask of packing into.The mixture that produces was refluxed＞6 hours.HPLC shows that all initiation materials 9 are consumed.Reactant mixture is cooled to ambient temperature and filtration.Solvent removed in vacuo.Residue is distributed between dichloromethane (105 milliliters) and the water (65 milliliters).With dichloromethane (30 milliliters) aqueous layer extracted.NaHSO with 5% 3The dichloromethane layer that aqueous solution (2x30 milliliter), water and brinish 1: 1 mixture (20 milliliters) and the washing of saline (2x20 milliliter) order merge.Solution is through MgSO 4Drying is filtered, and concentrate with the benzoic acid that produce 1.68 grams (2R, 3R)-4,4-two fluoro-5-iodo-2-(triphen methoxy) oxolanes-3-base ester 10.H 1NMR(CDCl 3)：δ3.44-3.57(dd，2H)，4.41(m，1H)，5.60-5.65(dd，1H)，6.95(d，1H)，7.21-8.15(m，20H)。
Method 2:
In the dark, with I 2(0.524 gram) and dichloromethane (8 milliliters) round-bottomed flask of packing into.At ambient temperature, with Ph 3P (0.634 gram) dropwise adds solution so far in the solution of dichloromethane (8 milliliters).Under this temperature, the suspension that stirring produces 30 minutes, and add imidazoles (0.734 gram).At room temperature, the suspension that produces stirred 5 minutes after, dropwise add lactonaphthol 8 (0.8 gram) in the solution of dichloromethane (8 milliliters), and at room temperature stir the solution that produces and spend the night.Add hexane (30 milliliters), stirred suspension is 10 minutes then, filter, and concentrate with the benzoic acid that produce 1.1 grams (2R, 3R)-4,4-two fluoro-5-iodo-2-(triphen methoxy) oxolanes-3-base ester 10.
(7) benzoic acid (2R, 3R, 5R)-5-(the amino 2-oxo pyrimidine-1 (2H)-yl)-4 of 4-, the preparation of 4-two fluoro-2-(triphen methoxy) oxolane-3-base ester
Figure GPA00001146396200141
Y′＝ClO 4，NO 3，CO 3
Under 125-130 ℃, with cytosine (9.5 gram), HMDS (26.3 gram) and (NH 4) 2SO 4The mixture heated of (250.2 milligrams) 4 hours.Remove excessive HMDS under the vacuum (60 holders, 125 ℃).With acetonitrile (30 milliliters) dissolving residue, then add Ag 2CO 3(4.6 grams, 1.1 equivalents).Under 60 ℃, the solution that stirring produces 30 minutes.Under 60 ℃, add above-mentioned iodide 10 (9.5 gram) in the solution of acetonitrile (10 milliliters).After 48 hours, reactant mixture is cooled to ambient temperature.After the processing, obtain 5.6: 1 the β of having of 9.8 grams: the rough title compound 11 of α ratio.H 1?NMR(CDCl 3)：δ3.52-3.63(dd，2H)，4.33(m，1H)，5.74(m，1H)，5.78(d，1H)，6.40(bt，1H)，7.21-8.15(m，22H)。
Reaction is also carried out under identical condition, except with 1, and 4-diox, toluene, EA, THF, DCE, propione, 1,3-dimethyl-3,4,5 is beyond 6-tetrahydrochysene-2 (1H)-pyrimidone, benzonitrile, propionitrile or the sulfolane replacement acetonitrile.In these solvents of major part, obtain high β: α than and/or the chemical compound 7 of the β-enrichmentization of high yield more.
In addition, at reaction, check various normal Ag 2CO 3(0.3,0.6 and 0.9 equivalent), various normal cytosine (3.5,7,10 and 15 equivalent) and all temps (50-80 ℃).The result shows, in these examples, obtains the chemical compound 11 of the β-enrichmentization of good yield.
Further, various concentration and various water content all produce the chemical compound 11 of the β-enrichmentization that needs.
(8) benzoic acid (2R, 3R, 5R)-5-(the amino 2-oxo pyrimidine-1 (2H)-yl)-4 of 4-, the preparation of 4-two fluoro-2-(methylol) oxolanes-3-base ester
Figure GPA00001146396200151
With crude compound 11 (16.3 gram) and acetonitrile (20 milliliters) round-bottomed flask of packing into.Dense HCl (6N, 3 milliliters) is added solution so far, and the suspension that produces was stirred 16 hours.Filter reaction mixture dilutes with EtOAc (30 milliliters) down at 45 ℃ then.Suspension filtered is also dry to produce the good β that has of 3.0 grams: the benzoic acid of α ratio (2R, 3R, 5R)-5-(4-amino-2-oxo pyrimidine-1 (2H)-yl)-4,4-two fluoro-2-(methylol) oxolanes-3-base ester 15.H 1NMR(DMSO-d 6)：δ3.73-3.84(dd，2H)，4.48(m，1H)，5.59(m，1H)，6.13(d，1H)，6.35(t，1H)，7.60(m，2H)，7.73(t，1H)，8.08(m，3H)，8.60(bs，1H)，9.60(bs，1H)。
(9) preparation of gemcitabine
Figure GPA00001146396200152
Use two kinds of methods that chemical compound 15 is changed into chemical compound 16.
Method 1:
Stir down, with chemical compound 15 (80.6 grams, 200 mMs) and MeOH (146 milliliters) round-bottomed flask of packing into.With the 7N NH among the MeOH (285.7 milliliters, 10 equivalents) 3Add suspension so far lentamente, and the suspension stirring that produces is spent the night.Remove in the vacuum and desolvate.Heating is dissolved in the residue that produces in the water (310 milliliters) down.With the aqueous solution that the t-butyl methyl ether washing produces, isolate multilamellar then.This method repeats several times, up to removing all Organic substances.Stir down, Linesless charcoal (7 gram) is added to aqueous solution.Under 40 ℃, added hot suspension 30 minutes, and make suspension filter (not cooling) through Celite pad.Volume is reduced to～45 milliliters, and under agitation, adds 2-aminopropane. (180 milliliters).At ambient temperature, stir down, dense HCl (6N, 105 milliliters) is added mixture so far.Then, the suspension that stirs is cooled to 0-4 ℃, and remains under 0-4 ℃ and spend the night.Filter the suspension that produces.With 4: 1 mixture (2x10 milliliter) washing solid residue of cold 2-aminopropane. and water, and the drying solid residue is to produce the gemcitabine 16 of 44.25 grams.H 1?NMR(D 2O)：δ3.79(dd，1H)，3.97(dd，1H)，4.05(m，1H)，4.30(m，1H)，6.16(m，1H)，6.22(d，1H)，7.95(d，1H)。
Method 2:
Stir down, with chemical compound 15 (8.3 grams, 20 mMs) and MeOH (14 milliliters) round-bottomed flask of packing into.With CF 3CH 2OH (5 milliliters) and K 2CO 3(2.6 gram) adds suspension so far.The suspension stirring that produces is spent the night.Except that after desolvating, heating is dissolved in the residue that produces in the water (310 milliliters) down in a vacuum, and with the t-butyl methyl ether washing several times.Separate water layer, and under agitation use Linesless charcoal (0.5 gram) to handle water layer.Under 40 ℃, added hot suspension 30 minutes, and make suspension filter (not cooling) through Celite pad.Volume is reduced to about 5 milliliters, and under agitation adds 2-aminopropane. (2 milliliters).At ambient temperature, dense HCl (6N, 10 milliliters) is added mixture so far.Then, suspension is cooled to 0-4 ℃, and remains under 0-4 ℃ and spend the night.After the filtration, with 4: 1 mixture (2x5 milliliter) washing solid residue of cold 2-aminopropane. and water, and the drying solid residue is to produce the gemcitabine 16 of 4.5 grams.H 1NMR(D 2O)：δ3.79(dd，1H)，3.97(dd，1H)，4.05(m，1H)，4.30(m，1H)，6.16(m，1H)，6.22(d，1H)，7.95(d，1H)。
Other specific embodiment
Disclosed all features of this description can make up with any combination.That disclosed each feature of this description can be used to is identical, quite or the similar purpose alternative features replace.Therefore, unless indication expressly in addition, the example of the general name series of the coordinate that disclosed each feature is a similar features.
From above-mentioned description, those skilled in the art can easily determine substitutive characteristics of the present invention, and is not breaking away under its spirit and scope, can carry out various changes and modifications of the present invention so that it adapts to various uses and condition.Therefore, other specific embodiment also is within the scope of the claims.

Claims (33)

1. the method for a preparation formula (I) beta-nucleosides chemical compound,
Figure FPA00001146396100011
Wherein:
R 1Be H, alkyl, aryl alkyl, alkyl diaryl silicyl, trialkylsilkl, diarye silyl, alkyl-carbonyl or aryl carbonyl;
R 2For RC (O)-, RR ' NC (O)-, ROC (O)-, RC (S)-, RR ' NC (S)-or ROC (S)-; R and R ' are H, alkyl, aryl, cycloalkyl, Heterocyclylalkyl or heteroaryl independently of one another; R 3And R 4Be H or fluorine independently of one another; And B is
Figure FPA00001146396100012
Wherein, R 5Be H, alkyl or aryl; R 6Be H, alkyl, thiazolinyl, halogen or aryl; X is N or C-R ", R " be H, alkyl, thiazolinyl, halogen or aryl; And Y is an amino protecting group; Described method is included in transition metal salt and exists down, makes the tetrahydrofuran-compound of formula (II):
Figure FPA00001146396100013
Wherein, R 1, R 2, R 3And R 4As above-mentioned definition, and L is fluorine, chlorine, bromine or iodine, and the nucleobase derivatives of following formula reaction:
Figure FPA00001146396100021
Wherein, R 5, R 6With Y such as above-mentioned definition, and Z is a hydroxyl protecting group.
2. the method for claim 1, wherein described transition metal salt is a silver salt.
3. method as claimed in claim 2, wherein, described transition metal salt is AgClO 4, AgNO 3Or Ag 2CO 3
4. the method for claim 1, wherein R 3And R 4The fluorine of respectively doing for oneself.
5. the method for claim 1, wherein R 1Be trityl, and L is I.
6. the method for claim 1, wherein R 2Be benzoyl.
7. the method for claim 1, wherein described nucleobase derivatives is
Figure FPA00001146396100022
8. the method for claim 1, wherein R 1Be trityl, (CH 3) 3C, alkyl diaryl silicyl, trialkylsilkl or diarye silyl; R 2For RC (O)-, R is an alkyl or aryl; And described transition metal salt is AgClO 4, AgNO 3Or Ag 2CO 3
9. method as claimed in claim 3, wherein, R 1Be trityl, and L is I.
10. method as claimed in claim 9, wherein, R 2Be benzoyl.
11. method as claimed in claim 10, wherein, described nucleobase derivatives is
Figure FPA00001146396100023
12. the method for claim 1, wherein described tetrahydrofuran-compound is
Figure FPA00001146396100031
Described nucleobase derivatives is
Figure FPA00001146396100032
Described transition metal salt is AgClO 4, AgNO 3Or Ag 2CO 3And described beta-nucleosides chemical compound is
Figure FPA00001146396100033
13. the method for claim 1 further comprises the chemical compound that described beta-nucleosides chemical compound is transformed an accepted way of doing sth (III):
Figure FPA00001146396100034
Wherein, R 3, R 4With B such as claim 1 definition.
14. method as claimed in claim 3 further comprises the chemical compound that described beta-nucleosides chemical compound is transformed an accepted way of doing sth (III):
Figure FPA00001146396100035
Wherein, R 3, R 4With B such as claim 1 definition.
15. method as claimed in claim 12 further comprises described beta-nucleosides chemical compound changed into down and shows chemical compound:
Figure FPA00001146396100036
16. the method for claim 1 further comprises, before reaction, with the lactone compound of following formula (IV):
Figure FPA00001146396100037
Wherein, R 3, R 4With B such as claim 1 definition, be reduced into the furanose chemical compound of following formula:
And
This furanose chemical compound is transformed the tetrahydrofuran-compound of an accepted way of doing sth (II).
17. method as claimed in claim 14 further comprises, before reduction, uses the chemical compound of acid treatment following formula:
Figure FPA00001146396100042
Wherein, R 3And R 4Be H or halogen independently of one another; R 7Be H, alkyl, aryl, cycloalkyl, assorted alkyl or heteroaryl; And R 8And R 9Be H or hydroxyl protecting group independently of one another, or R 8And R 9Be C together 1-3Alkylidene;
Make from the chemical compound reaction of the product and the following formula of above-mentioned processing generation:
R 1-L’，
Wherein, R 1Be alkyl, aryl alkyl, alkyl diaryl silicyl, trialkylsilkl, diarye silyl, alkyl-carbonyl or aryl carbonyl; Reaching L ' is leaving group, to produce the chemical compound of formula V:
Wherein, R 1, R 3And R 4As above-mentioned definition; And
The chemical compound of formula V is transformed the chemical compound of an accepted way of doing sth (IV).
18. method as claimed in claim 17, wherein, R 2Be benzoyl, and L ' is chlorine, bromine or iodine.
19. method as claimed in claim 18, wherein, R 1Be trityl, R 3And R 4The fluorine of respectively doing for oneself, and B is
Figure FPA00001146396100044
20. method as claimed in claim 19 further comprises the chemical compound that described beta-nucleosides chemical compound is transformed an accepted way of doing sth (III):
Figure FPA00001146396100051
Wherein, R 3, R 4With B such as claim 1 definition.
21. the chemical compound of a formula (VI):
Figure FPA00001146396100052
Wherein,
R 1Be trityl, benzyl, (CH 3) 3C, alkyl diaryl silicyl, trialkylsilkl or diarye silyl;
R 2Be H, alkyl-carbonyl or aryl carbonyl; And
R 3And R 4Be H or halogen independently of one another.
22. chemical compound as claimed in claim 21, wherein, R 3And R 4The fluorine of respectively doing for oneself.
23. chemical compound as claimed in claim 22, wherein, R 1Be trityl, and R 2Be H.
24. chemical compound as claimed in claim 22, wherein, R 1Be trityl, and R 2Be benzoyl.
25. chemical compound as claimed in claim 22, wherein, R 2Be H.
26. the chemical compound of a formula (VII):
Figure FPA00001146396100053
Wherein,
R 2' be alkyl-carbonyl or aryl carbonyl;
R 3And R 4Be H or halogen independently of one another; And
B is
Figure FPA00001146396100061
Wherein, R 5Be H, alkyl or aryl, R 6Be H, alkyl, thiazolinyl, halogen or aryl, X is N or C-R ', and R ' is H, alkyl, thiazolinyl, halogen or aryl, and Y is amino protecting group or Bronsted acid.
27. chemical compound as claimed in claim 26, wherein, R 3And R 4The fluorine of respectively doing for oneself.
28. chemical compound as claimed in claim 27, wherein, R 2' be benzoyl.
29. chemical compound as claimed in claim 28, wherein, B is Or
Figure FPA00001146396100063
30. chemical compound as claimed in claim 26, wherein, described chemical compound has following spatial chemistry:
Figure FPA00001146396100064
31. chemical compound as claimed in claim 30, wherein, R 3And R 4The fluorine of respectively doing for oneself.
32. chemical compound as claimed in claim 31, wherein, R 2' be benzoyl.
33. as the chemical compound of claim 32, wherein B is
Figure FPA00001146396100065
Or
Figure FPA00001146396100066
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